The SARS-CoV-2, the causative agent of COVID-19, has been established to gain access to the human cell via the ACE2 receptor similar to its familial coronavirus SARS-CoV which led to the outbreak in 2003. A concern with the newer 2019 coronavirus is its 10-20-fold higher affinity to the ACE2 receptor that of SARS-CoV, aiding its effective human-to-human transmission which has led to this pandemic. ACE2 receptor expression is thought to be upregulated in use with ACE inhibitors. As ACE inhibitors are known to be a used extensively in the treatment of hypertension it was a concern regarding the risk of using these medications alongside a SARS-COV-2 infection. ACE inhibitors are also used in the treatment regime of other common conditions including diabetes and Cardiovascular disease (CVD). It is worth noting that ACE2 expression has found to be upregulated by the use of thiazolidinediones and ibuprofen too. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. Therefore, it would hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs would increase the risk of developing severe and fatal COVID-19.

The pandemic outbreaks of coronavirus disease 2019 (COVID-19) was first discovered in Wuhan, Hubei, China in December 2019. The COVID-19 was caused by the novel coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It took 30 days to spread to all provinces of China [1]. Recently, the confirmed cases of COVID-19 have been reported from about 200 countries or regions on March 30, 2020, and killed almost 30 thousand people [2]. Efficient identification of the infection by SARS-CoV-2 has been one of the most important tasks to facilitate all the following counter measurements in dealing with infectious disease. In Taiwan, a COVID-19 Open Science Platform adhering to the spirit of open science: sharing sources, data, and methods to promote progress in academic research while corroborating findings from various disciplines has established in mid-February 2020, for collaborative research in support of the development of detection methods, therapeutics, and a vaccine for COVID-19. Research priorities include infection control, epidemiology, clinical characterization and management, detection methods (including viral RNA detection, viral antigen detection, and serum antibody detection), therapeutics (neutralizing antibody and small molecule drugs), vaccines, and SARS-CoV-2 pathogenesis. In addition, research on social ethics and the law are included to take full account of the impact of the COVID-19 virus.

Nitric oxide (NO) is a unique signaling molecule in the mammalian species. NO is produced by a variety of cell types to elicit distinct physiological actions. In the vascular system, NO is produced by the endothelium, a single layer of cells forming the inner lining of all blood vessels. Endothelium-derived NO has several different functions, one of which is vascular smooth muscle relaxation, resulting in vasodilation and a consequent decrease in blood pressure and increase in local blood flow. In the erectile tissue, NO is released as a neurotransmitter from the nerves innervating the corpus cavernosum during sexual stimulation, and causes profound smooth muscle relaxation and increased blood flow to the erectile tissue. This results in engorgement with blood and consequent penile erection.The uniqueness of NO as a signaling molecule derives, at least in part, by the fact that it is a gaseous molecule in its native state. However, despite being a gas, NO, like oxygen (O2), elicits its pharmacological effects as a solute in aqueous solution. Another unique characteristic of NO is its fleeting action because of its highly unstable chemical nature and reactivity. Unlike many other signaling molecules, NO elicits its wise array of physiological effects by distinct mechanisms. For example, vascular and nonvascular smooth muscle relaxation, and inhibition of platelet function are mediated by intracellular cyclic GMP (cyclic 3’, 5’-guanosine monophosphate). NO elicits many cyclic GMP-independent effects as well. For example, nitric oxide is a reactive free radical that can covalently modify protein function. One good example is protein S-nitrosylation, which can result in both regulatory and aberrant effects. By this and a variety of other mechanisms, NO also reacts with other molecules, such as reactive oxygen species, in invading cells such as bacteria, parasites and viruses to kill them or inhibit their replication or spread.The first pharmacological action of nitric oxide, demonstrated several years before it’s production in mammals was actually discovered, was vascular and nonvascular smooth muscle relaxation. One of many examples of the latter is the smooth muscle enveloping the sinusoidal cavities within the corpus cavernosum. Another important example is the airway smooth muscle in the trachea and bronchioles of the lungs. Indeed, inhalation of NO gas causes bronchodilation and increased delivery of air into the lungs. However, perhaps more significant than the bronchodilator effect of inhaled NO is its vasodilator effect. In fact, advantage was taken of the vasodilator action of NO in the lungs by Warren Zapol, MD, from the Massachusetts General Hospital in Boston, who discovered that inhalation of very small amounts of NO gas by newborn babies with life-threatening, persistent pulmonary hypertension (PPHN) results in a dramatic and permanent reversal of pulmonary vasoconstriction. Inhaled NO (INO) literally turned blue babies into pink babies. Without INO, most babies would have died while others would have required highly invasive procedures (extracorporeal membrane oxygenation; ECMO) to oxygenate their lungs, and may not have survived.Regarding its antiviral action, NO has been shown to increase the survival rate of mammalian cells infected with SARS-CoV (Severe Acute Respiratory Syndrome caused by coronavirus). In an in vitrostudy, NO donors (i.e., S-nitroso-N-acetylpenicillamine) greatly increased the survival rate of SARS-CoV-infected eukaryotic cells, suggesting direct antiviral effects of NO (1). In this study, NO significantly inhibited the replication cycle of SARS CoV in a concentration-dependent manner. NO also inhibited viral protein and RNA synthesis. Furthermore, NO generated by inducible nitric oxide synthase inhibited the SARS CoV replication cycle. The coronavirus responsible for SARS-CoV shares most of the genome of COVID- 19 indicating potential effectiveness of inhaled NO therapy in these patients.In 2004, during the SARS-CoV outbreak in China, the administration of inhaled NO reversed pulmonary hypertension, improved severe hypoxia and shortened the length of ventilatory support as compared to matched control patients with SARS-CoV (2). The mechanism of action was thought to be pulmonary vasodilation and consequent improved oxygenation in the blood of the lungs, thereby killing the virus, which does not do well in a high oxygen environment. In addition, however, I would offer the opinion that the NO also interacts directly with the virus to kill it and/or inhibit its replication, as shown in a prior study (1).Although studies have not yet been reported with COVID-19, NO has been shown to have an antiviral effect on several DNA and RNA virus families (3). The NO-mediated S-nitrosylation of viral molecules might be an intriguing general mechanism for the control of the virus life cycle. In this regard, it is conceivable that NO could nitrosylate cysteine-containing enzymes and proteins, including nucleocapsid proteins and glycoproteins, present in the coronavirus.In view of the knowledge gained by treating SARS-CoV patients with INO, it follows that INO might be effective in patients with the current SARS CoV-2 (COVID-19) infection. Indeed, a clinical trial of inhaled nitric oxide in patients with moderate to severe COVID-19 with pneumonia and under assisted ventilatory support recently received IRB (Institutional Review Board) approval at the Massachusetts General Hospital. Warren Zapol is director of this project. This trial has now been expanded to include at least two additional hospitals in the U.S. In the successful treatment of persistent pulmonary hypertension in newborns, the amount of NO inhaled is generally one ppm (part per million). In the clinical trial using COVID-19 patients, the amount of NO will be approximately 100-fold higher, about 100 ppm. This is a safe dose of INO, which could prove to be effective in killing the virus and allowing recovery of the patient. The effective use of INO would also lessen the need for oxygen, ventilators, and beds in the ICU.One thing I urge everyone to practice during this coronavirus pandemic is to breathe or inhale through your NOSE and exhale through your mouth. Swedish investigators at the Karolinska Institute in Stockholm have shown that the cells and tissues in the nasal sinusoids, but not the mouth, constantly and continuously produce nitric oxide, which is a gas, and can be easily detected in the exhaled breath. The physiological significance of this is that nasally-derived NO, when inhaled through the nose, improves oxygen delivery into the lungs by causing bronchodilation. This physiological action of inhaled NO is well-known by competitive athletes, especially runners. Moreover, when inhaling through the nose, your nasal nitric oxide is inhaled into your lungs where it stands a chance of meeting up with the coronavirus particles and killing them or inhibiting their replication. Inhaling through your mouth will NOT accomplish this. By the same token, exhaling through your nose is highly wasteful in that you would be expelling the NO away from the lungs, where it is needed most.“INHALE THROUGH YOUR NOSE, AND EXHALE THROUGH YOUR MOUTH!”

Lopinavir combined with ritonavir were reported to benefit the patients with SARS by reducing the viral loads. However, in the latest clinical trials, no benefit was observed with lopinavir-ritonavir treatment beyond standard care in patients with COVID-19. We comment here that this disappointed result of clinical trial might result from the low volume of the lung distribution of lopinavir. The major reasons were listed below: 1) The binding affinity of ACE2 with SARS-CoV-2 spike protein is ~10- to 20-fold higher than the binding affinity of ACE2 with SARS-CoV spike protein, indicating that SARS-CoV-2 can enter AT2 cells in lung much easier than SARS-CoV. Therefore, the viral loads of SARS-CoV-2 might be much higher than viral loads of SARS-CoV in the lung tissue. 2) The concentration of lopinavir in the lung tissue was 1.18 μg equiv/ml in rats. The low volume of the lung distribution of lopinavir might not be enough to inhibit the coronavirus replication due to the high viral loads in the lung tissue. 3) In contrast, the concentration of chloroquine in the lung tissue was much higher (30.76 ± 0.85 μg equiv/ml) in rats, which might lead to its clinical and virologic benefits in the treatment of COVID-19 patients. Together, we proposed here that anti-SARS-CoV-2 drug repurposing studies should pay more attentions to the lung tissue distribution of antiviral drugs. The efficacy of antiviral drugs might depend on their lung tissue distributions

COVID-19 is a disease which is sweeping the globe, often with devastating consequences. The more we understand, the more it appears that infection has a very wide clinical spectrum from totally asymptomatic to life threatening. Without widespread community testing it is impossible to ascertain true infection rates and develop strategies which reduce or prevent transmission without the need for on-going draconian measures such as complete national lockdown. These measures are mandatory at the time of writing, however widespread adoption of face masks has been shown to help prevent transmission of other respiratory pathogens, and also infections acquired by healthcare staff. Combining mass testing with a combination of social distancing and face mask use might offer a way forward until a mass COVID-19 vaccination programme can be established.

The current Covid-19 pandemic is a significant global health threat. The outbreak has profoundly affected all healthcare professionals, including heart surgeons. To adapt to these exceptional circumstances, cardiac surgeons had to change their practice significantly. We herein discuss the challenges and broad implications of the Covid-19 pandemic from the perspective of the heart surgeons.

Angiotensin converting enzyme-2 (ACE2) is the receptor for the coronavirus SARS-CoV-2, which causes COVID-19. We propose the following hypothesis: Imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing Angiotensin-II (ANG II) signaling, a primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of ANG II to ANG peptides that counteract pathophysiological effects of ACE1-generated ANGII. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: 1) ANG II receptor blockers (ARBs); 2) ACE1 inhibitors (ACEIs); 3) Agonists of receptors activated by ACE2-derived peptides [e.g., ANG (1-7), which activates MAS1]; 4) Recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved ARBs and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19.

In this review, we identify opportunities for drug discovery in the treatment of COVID-19 and in so doing, provide a rational roadmap whereby pharmacology and pharmacologists can mitigate against the global pandemic. We assess the scope for targetting key host and viral targets in the mid-term, by first screening these targets against drugs already licensed; an agenda for drug re-purposing, which should allow rapid translation to clinical trials. A simultaneous, multi-pronged approach using conventional drug discovery methodologies aimed at discovering novel chemical and biological means targetting a short-list of host and viral entities should extend the arsenal of anti-SARS-CoV-2 agents. This longer-term strategy would provide a deeper pool of drug choices for future-proofing against acquired drug resistance. Second, there will be further viral threats, which will inevitably evade existing vaccines. This will require a coherent therapeutic strategy which pharmacology and pharmacologists are best placed to provide.

Background: Fangcang hospital (cabin hospitals) played a key role in isolation and control of the infection sources during COVID-19 epidemic. The patients at Fangcang hospitals were complicated, and many had different symptoms of COVID-19, some had comorbidities or mental stress, and many were confused with the drug usages etc. Objective: Due to the limitation and high work pressure of first line medical workers, patients’ various problems couldn’t be explained well. Under this circumstance, online pharmaceutical care was provided by clinical pharmacists. This study was a retrospective study to evaluate the role and usefulness of clinical pharmacists at Jianghan Fangcang Hospital. Besides, this new mode of service was also introduced in detail to provide options for pharmacists in other hospitals. Methods: The pharmaceutical care included medication education via broadcast station, and medication reconciliation, optimization of drug use, monitor of adverse drug events, and psychological comfort via WeChat® one-to-one service. In this study, we analyzed patients’ characteristics and drug usages, concluded almost 200 patients’ problems classified into 6 aspects solved by clinical pharmacists, and also assessed the patients’ satisfaction with our service. Results: The clinical pharmacist help patients solved almost 200 questions, which mainly focused on the drug related problems including drug usage (65.38%), medication reconciliation (55.13%), drug precautions (23.1%), adverse drug reactions (35.9%), and psychological counseling (32.05%). Through 35 days’ services, Most patients were satisfied with clinical pharmacist service(66.7%great, 18.0%good). Besides, most patients thought the service had positive effect on their mental stress(16.7%great, 43.6%good, 26.9%fair). Conclusion: The results of the retrospective study indicated that clinical pharmacist can effectively reduce and prevent drug-related, life-related and COVID-19-related problems for COVID-19 patients. This work may provide possible work patterns for clinical pharmacist in other hospital and give more professional service for Fangcang hospital patients.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML), and currently in patients with CML in chronic phase (CML-CP) the first-line treatment is based on BCR-ABL targeted therapy with TKIs [1]. Although generally well tolerated, all BCR-ABL TKIs can be associated with hematologic and non-hematologic toxicities [2]. Most of the patients with CML-CP continue receiving TKIs, unless there is lack of optimal response and/or serious toxicities.

Background and Purpose: Resurgence in the use of chloroquine as a putative treatment for COVID-19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity. Experimental Approach: In vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine, alone, or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone-anaesthetised rats and rabbits. Randomised, controlled interventional studies in rats assessed diazepam, clonazepam and Ro5-4864 administered: (i) prior, (ii) during, and (iii) after chloroquine; and the effects of diazepam: (iv) at high dose, (v) in urethane-anaesthetised rats, and (vi) co-administered with adrenaline. Key Results: Chloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose-dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between interventions and control. Diazepam increased heart rate in study (iv) and, as with clonazepam, also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia. Conclusion and Implications: Neither diazepam, nor other ligands for benzodiazepine binding sites, protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity.

The new corona virus has become a global health concern.Voice has the potential to provide an easily obtained, non-invasive way to monitor physiological changes throughout the body. For health care providers with experience in the clinical management of patients with COVID-19 and other viral infections, including SARS and MERS, as well as sepsis and ARDS, the application of acoustical voice analysis should serve as a foundation for optimized supportive care to ensure the best possible chance for survival.

The COVID-19 outbreak is a global pandemic with rapid community spread. Patients with multi-morbidities are particularly vulnerable during this time. The number of cases soared in early February 2020, and Singapore declared escalation of the Disease Outbreak Response System Condition (DORSCON) level to Orange. Multiple measures have been taken to combat the spread of this highly contagious infection. Despite our medical manpower being diverted to the wards, our hospital aims to maintain nearly full operations at the clinic, balancing against concern about the spread of the virus and exposing healthcare workers to potential risks. We describe the measures taken in a tertiary hospital in Singapore to mitigate the risk of infection in the outpatient setting while ensuring that continuing clinical care of patients with chronic diseases is not compromised.

Starting from December 2019 the novel SARS-Cov-2 has spread all over the world, being recognized as the causing agent of COVID-19. Since nowadays no specific drug therapies neither vaccines are available for the treatment of COVID-19, drug repositioning may offer a strategy to efficiently control the clinical course of the disease and the spread of the outbreak. In this paper we aim to describe the main pharmacological properties, including data on mechanism of action, safety concerns and drug-drug interactions, of drugs currently administered in patients with COVID-19, focusing on antivirals and drugs with immune-modulatory and/or anti-inflammatory properties. Where available, data from clinical trials involving patients with COVID-19 were reported. A large number of clinical studies have been registered worldwide and several drugs were repurposed to face the new health emergency of COVID-19. For many of these drugs, including lopinavir/ritonavir, remdesivir, favipiravir, chloroquine and tocilizumab, clinical evidence from literature and real life settings support their favorable efficacy and safety profile in improving patients’ clinical conditions. Even though drug repurposing is necessary, it requires caution. Indeed, too many drugs that are currently tested in patients with COVID-19 have peculiar safety profiles. While waiting for the results of clinical studies demonstrating the efficacy of drugs able to reduce symptoms and complications of COVID-19, the best therapeutic path to pursue is the development of an effective vaccine able to prevent this infection.

Coronavirus disease 2019 (COVID-19) is a remarkably challenging health issue that provoked all the health-care providers to contemplate some measures about the situation. All the health-care workers frontline (esp. emergency service, pulmonologists, infection disease specialist and anesthesiologist) have produced recommendations on prevention and taking care of COVID-19 patient (1,2). Whereas, at the second line another important issue is the ongoing healthcare for the continual disease situations.There are two main critical issues on cardiovascular surgery in this pandemic. Firstly, to delay the elective surgeries is essential to sustain the health-care service. Elective case triage is trickier for cardiovascular procedures which are relatively progressive conditions. Definitive decision to defer a procedure should be made regarding firstly to the capacity of health-care system, and then availability of surgical/anesthesia staff, intensive care unit beds, need for isolation beds, ventilators, cardiopulmonary bypass machine, extracorporeal membrane oxygenator, supplies such as sutures, grafts, valves and blood and blood product availability. The patient status should be taken into account to defer or to perform the procedure, as well. Therefore, we developed “Level of Priority” (LoP) statement for cardiovascular procedures (3). Elective cases are defined as LoP I that may be postponed as much as possible. LoP II to IV cases should be reconsidered by individual basis by “Heart Team”. The situations that can be managed by percutaneous coronary intervention, endovascular procedures and etc. may be handled by non-operative manners.The second one is the personal protection equipment and infection measures while dealing with a suspected / confirmed COVID-19 patient. It is obvious that a suspected / confirmed COVID-19 patient ought to be assessed with specific measures for any medical or surgical intervention. Personal protection equipment (PPE) is the most crucial measure during the pandemic. It is recognized that many centers are facing PPE shortages and there are recommendations to re-sterile the masks to be effective for reuse.(4) More measures should be taken into consideration for sterile environment such as surgical procedures. Some added measures such as face shield may be recommended for surgical procedures. The surgical team who scrubbed in, must wear extra equipment such as surgical coat and double gloves. It may be recommended to fix the long-sleeve gloves to the surgical coat by adhesive drapes (3). It is obvious that this kind of working environment with all this equipment is challenging, sometimes irritating and disquieting. One other big problem is the fraught feeling of health-care providers to be diseased or to be contagious for their family. Therefore, health-care providers may need enormous support for burnouts during the pandemic.The other measures such as preparation of the operating room (OR), anesthesiologic management, transportation of patients and disinfection of OR were discussed in the referring article (3).In conclusion, it is important to assess the “Level of Priority” for surgical procedures to support the service of health-care facility. More than that, whole surgical team should be protected by adequate PPE and should take the time to get full protected.

Naso-pharyngeal discharge as the first symptom of COVID-19 infection is presented in two cases . Appropriate diagnosis and isolation of the patients who may be at risk for covid-19 such as these cases help reduce further transmission.

The incidence of mechanical complications of acute coronary syndromes (ACS) needing cardiac surgery has reduced significantly in the last years due to early diagnosis and treatments. Covid-19 pandemic, however, would generate in the patients a sense of fear regarding access to the ERs so they probably underestimate symptoms such as chest pain or angina equivalents until situation does not became critical. In this way, this behaviour could create a vast pool of patients who will enter the hospital in much more critical situations and with mechanical complications of an evolving ACS needing cardiac surgery treatment.

A global coronavirus (COVID-19) pandemic occurred at the start of 2020 and is already responsible for more than 74,000 deaths worldwide, just over 100 years after the influenza pandemic of 1918. At the center of the crisis is the highly infectious and deadly SARS-CoV-2, which has altered everything from individual daily lives to the global economy and our collective consciousness. Aside from the pulmonary manifestations of disease, there are likely to be several electrophysiologic (EP) sequelae of COVID-19 infection and its treatment, due to consequences of myocarditis and the use of QT-prolonging drugs. Most crucially, the surge in COVID-19 positive patients that have already overwhelmed the New York City hospital system requires conservation of hospital resources including personal protective equipment (PPE), reassignment of personnel, and reorganization of institutions, including the EP laboratory. In this proposal, we detail the specific protocol changes that our EP department has adopted during the COVID-19 pandemic, including performance of only urgent/emergent procedures, afterhours/7-day per week laboratory operation, single attending-only cases to preserve PPE, appropriate use of PPE, telemedicine and video chat follow-up appointments, and daily conferences to collectively manage the clinical and ethical dilemmas to come. We discuss also discuss how we perform EP procedures on presumed COVID positive and COVID tested positive patients in order to highlight issues that others in the EP community may soon face in their own institution as the virus continues to spread nationally and internationally.

As Dr. Thomson eloquently notes in his valuable letter [1], underlying respiratory diseases appear to be less of a risk factor for poor outcome in COVID-19 patients than either underlying cardiovascular disease or diabetes. This intriguing finding emerged from several studies that examined underlying medical conditions in COVID-19 patients.In a single-center retrospective analysis of critically ill adults admitted to the intensive care unit of a hospital from China between late December 2019 and January 26, 2020, 22% of the non-survivors had cerebrovascular disease, 22% had diabetes, and 6% had chronic respiratory disease [2]. The analysis of data from patients with laboratory-confirmed COVID-19 from hospitals in China through January 29, 2020 found that 16.2% of those with serious disease had diabetes, 23.7% had hypertension, and 3.5% had chronic obstructive pulmonary disease [3]. A study of electronical medical records of COVID-19 patients admitted between January 16 and February 3, 2020 to a hospital from Wuhan found that hypertension and diabetes mellitus, the most common comorbidities, were present in 37.9%, 13.8%, of the patients with severe disease, respectively, but only in 3.4% of the patients with chronic obstructive pulmonary disease [4]. Finally, an analysis of all COVID-19 cases reported through February 11, 2020, extracted from the Infectious Disease Information System in China, found that case fatality rates in individuals with cardiovascular disease, chronic respiratory disease, and diabetes were 10.5%, 6.3%, and 7.3% respectively, as compared to 0.9% among patients with no comorbidities [5]. In a case series of COVID-19 patients hospitalized in Wuhan, China, ICU patients were more likely to have underlying diabetes than patients that did not receive ICU care (22.2% vs 5.9%) [6].The studies mentioned above did not stratify patients by therapies they were receiving. However, one commonality between cardiovascular disease and diabetes is that they are often treated with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-I receptor blockers (ARBs), widely used to inhibit the formation and action of angiotensin II.ACE shares 42% amino acid identity with ACE2 [7], a membrane-bound aminopeptidase [8] extensively expressed on type II human alveolar cells [9]. The genes encoding these two proteins are thought to have emerged by duplication [10]. ACE2 is distributed on many tissues and shows highest expression levels in the heart, kidney, lung, small intestine, and testis [11]. On the apical surface of polarized respiratory epithelial cells, ACE2 is a crucial and primary receptor for the cellular entry of SARS-CoV, the virus that caused the 2002-2003 SARS outbreak [12-16]. SARS-CoV binding to ACE2 mediates entry into human or animal cells [17]. ACE2 is also the receptor for SARS-CoV-2, the etiologic agent of COVID-19 [18]. Structural analyses indicate that SARS-CoV-2 binds the ACE2 receptor with a 10-20-fold higher affinity than SARS-CoV [19, 20].The entry of SARS-CoV and SARS-CoV-2 into their target cells is mediated by the viral spike (S) glycoprotein, which is located on the outer envelope of the virion [21]. The S glycoprotein has two functional subunits, S1, which binds the cellular receptor, and S2, which contains domains required for the fusion between viral and cellular membranes [22, 23]. Viral binding and membrane fusion represent the initial and critical steps during the infection cycle of the coronavirus [24] and the first step in establishing the infection [25, 26]. Binding is followed by internalization of ACE2 and down‐regulation of its activity on the cell surface [27-29].SARS-CoV binds ACE2 through a region of the viral S1 subunit called the minimal receptor-binding domain (RBD) [17]. RBD is the most important determinant of the SARS-CoV host range, and studies about the “species jump” during the 2002-2003 SARS outbreak revealed that changes of only one or two amino acids in this region were sufficient to make the virus “jump” to a new host [26, 30, 31].ACE and ACE2 are two members of the renin angiotensin system that negatively regulate each other [32, 33] and are distinct in their substrate specificity and function [34]. ACE converts angiotensin I to angiotensin II and mediates aldosterone release, vasoconstriction, sodium retention, cell proliferation, and organ hypertrophy [35]. ACE2 cleaves a single residue from angiotensin I to form angiotensin-(1-9), and a single residue from angiotensin II to form angiotensin-(1-7). In humans, ACE2 has a 400-fold higher catalytic efficiency when it uses angiotensin II as a substrate as compared to when it uses angiotensin I [36]. ACE2 and angiotensin-(1-7), through the Mas receptors, oppose ACE and mediate vasodilation and anti-proliferative, anti-hypertrophic, cardioprotective, and reno-protective effects [8, 35, 37]. ACE2 has physiological and pathological importance [25] and its dysregulation was implicated in heart disease, hypertension, and diabetes [36, 38-40]. ACE2 is not inhibited by ACE inhibitors [32] and several studies indicate that the ACE2/Angiotensin-(1-7)/Mas axis has anti-inflammatory effects [41, 42].It was recently hypothesized that treatment with ACE inhibitors and/or ARBs may lead to ACE2 overexpression and this could increase the risk of severe COVID-19 [43], possibly by increasing the internalization of SARS-CoV-2. Several lines of evidence indicate that pharmacological manipulation of the renin-angiotensin-aldosterone pathway could affect ACE2 receptor levels. In animal studies, the selective blockade of angiotensin II synthesis or activity increased cardiac Ace2 gene expression and activity [44, 45], and treatment with ARBs increased the levels of cardiovascular ACE2 receptors [46-49]. While this link is thought-provoking as a possibility, there isn’t currently sufficient evidence to contemplate changing patients’ existing therapeutic regimens in order to minimize their risk of COVID-19 complications. The first clinical evidence exploring this link indicated that the use of ACEI and ARBs appear to improve the clinical outcome of COVID-19 patients with hypertension [50]. We will only learn about any possible associations, along with their magnitude and direction, from carefully conducted and adequately powered clinical trials.It is also important to consider that an increase in ACE2 levels does not necessarily entail a negative impact for the course of COVID-19. ACE2, by forming angiotensin-(1-7) from angiotensin II, could diminish the deleterious effects of angiotensin II and, consequently, it is also possible that ACE inhibitors or ARBs could, in fact, lower the risk of complications [51]. However, increased ACE2 and the formation of angiotensin-(1-7), by inhibiting COX-2, could exert anti-inflammatory effects [52, 53], underscoring the multitude of possible effects and the need to conduct studies to interrogate these connections. Finally, it is not known whether an increase in the expression of ACE2 would also lead to an increased shedding and increased levels of soluble ACE2, which could act as a decoy receptor and lower viral entry into cells [54]. In support of this, recombinant human ACE2 ameliorated the lung injury induced by the avian influenza H5N1 virus in mice [55]. It is also important to consider that from the relatively limited amount of human data, plasma ACE2 activity does not appear to be statistically different between individuals taking ACE inhibitors or ARBs and those not taking these medications, but these results do not reflect the levels of cellular receptors [56]. Structural analyses indicate that the binding of the SARS-CoV spike protein to ACE2 does not occlude the catalytically active site of the receptor [26, 57], and it was hypothesized that angiotensin II binding to ACE2 could induce a conformational change in the receptor, which will no longer be favorable for SARS-CoV-2 binding [54]. The mining of existing datasets, preclinical studies, and clinical trials will help shed light on these complex and sometimes conflicting scenarios.A decrease in the number of ACE2 receptors appears to be involved in acute lung injury and cardiovascular pathology [58, 59], and may be detrimental during coronavirus infection. A mouse Ace2 knockout developed severe cardiac contractility defects and increased angiotensin II levels, and the additional deletion of Ace rescued this phenotype [60]. In acute lung injury models, the loss of Ace2precipitated severe acute lung failure, and this was attenuated by the exogenous recombinant human ACE2 in both Ace2 knock-out and in wild-type mice [59]. Attenuation of the Ace2 catalytic function perturbed the pulmonary renin-angiotensin-aldosterone system and increased inflammation and vascular permeability [61], and Ace2 overexpression decreased lung inflammation in an animal model of acute lung injury [62]. In vitro and in experimental animals, SARS-CoV and the SARS-CoV spike protein downregulated ACE2 expression [12, 28]. In mice with lung injury, injection of the SARS-CoV spike protein worsened the acute lung failure and caused lung edema, increased vascular permeability, and decreased lung function, and this pathology was attenuated by blocking the renin-angiotensin-aldosterone pathway [12]. Thus, animals infected with SARS-CoV or treated with the spike protein resemble Ace2 knockout animals [12]. It is relevant that a pilot study of patients with acute respiratory distress syndrome reported the accumulation of angiotensin I and the decrease of angiotensin-(1-9), indicating decreased ACE2 activity, among non-survivors [63]. Thus, SARS-CoV and SARS-CoV-2 might contribute to severe respiratory symptomatology partly because the viruses, by binding the ACE2 receptors, also deregulate protective pathways in the lungs.Thus, either increased or decreased numbers of pulmonary ACE2 receptors may be detrimental during SARS-CoV or SARS-CoV-2 infection, most likely for distinct reasons. An increased number of ACE2 receptors may lead to a higher viral load and more severe clinical disease. Diabetes increases ACE2 expression, as shown in several experimental models, and the resulting increased viral load might explain the more severe course of COVID-19 in diabetic patients [64, 65]. Interestingly, in a rodent model of diabetes, ibuprofen inhibited the ACE/angiotensin II/angiotensin type 1 receptor axis and enhanced the ACE2/angiotensin-(1-7)/Mas receptor axis [66]. Too few functional ACE2 receptors, which decrease even more as a result of high viral loads and enhanced receptor internalization [67], might exacerbate acute lung injury, increase angiotensin II levels, and alter the balance between pro- and anti-inflammatory responses. It is relevant that in a study on twelve COVID-19 patients from China, plasma angiotensin II levels were markedly elevated as compared to healthy control individuals, and linearly associated with the viral load and with the lung injury [68]. The animal studies that documented an age-dependent decrease in ACE2 expression in the lung and the aortic might also explain, at least in part, the age-dependent increase in the risk of serious COVID-19 complications [69, 70].SARS-CoV can also bind cells through alternative receptors that include the C-type lectins DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) and/or L-SIGN (liver/lymph node-SIGN) [14, 71-73]. It will be critical to understand the potential involvement of the same, or alternative receptors in the pathogenesis of COVID-19.It has been less clear why SARS-CoV and SARS-CoV-2 lead to severe lung disease [57], in contrast to other, previously known coronaviruses, which usually result in mild upper respiratory infections and cause pneumonia only rarely, mostly in newborn, the elderly, and immunocompromised individuals [74-77]. One of the possibilities advanced for SARS is that the burden of viral replication and the immune status of the host may both shape the severity of the infection [57, 78, 79]. The same might be true for COVID-19, and further exploring the link between viral burden, chronic medical conditions, long-term medication usage, and the severity of the infection will be critical.An important lesson from SARS and MERS is the association between the incubation period and disease severity. For any infectious disease, the incubation period varies among individuals, even for the same outbreak, and depends on the initial infective dose, the speed of pathogen replication within a host, and host defense mechanisms [80]. During the 2002-2003 SARS outbreak, a study in Hong Kong revealed that patients with shorter incubation times developed more severe disease [81]. The same was found in MERS patients from South Korea, where longer incubation times were associated with a lower risk of death [82]. Interestingly, during the SARS outbreak in Hong Kong, healthcare workers, who have a higher infecting dose, had 34% shorter median incubation times than non-healthcare workers [83]. It will be interesting to examine whether the same is true for SARS-CoV-2, and whether the incubation period is different in COVID-19 patients when they are stratified by age, coexisting morbidities, and therapies they receive for chronic diseases. While the association between the incubation period and mortality might simply indicate that the disease was confirmed earlier in patients with longer incubations, and reflect earlier treatment opportunities [82], it is also plausible that high viral loads might mediate the link between the two.Two factors decisive for the successful control of outbreaks are the ability to isolate asymptomatic individuals and the ability to trace and quarantine their contacts [84, 85]. Several studies reported asymptomatic shedding of SARS-CoV-2, indicating that asymptomatic carriers, or individuals with very mild symptoms, may sustain transmission [86-89]. For example, nearly 18% of the passengers who tested positive for SARS-CoV-2 on the Diamond Princess cruise ship were asymptomatic [88]. Another valuable finding that emerged from the COVID-19 outbreak analysis in Singapore, and has a strong impact on infection control, is that after becoming asymptomatic, some patients continued to shed the virus for up to several days. In one instance, a patient continued to have detectable respiratory shedding, as shown by PCR, for eight consecutive days after becoming asymptomatic [90]. Another study revealed that several children with COVID-19 persistently tested positive for viral RNA on fecal swabs after their nasopharyngeal cultures became negative. Even though replication-competent virus was not detected in the fecal swabs, this finding leaves open the possibility of SARS-CoV-2 fecal-oral transmission [91]. These findings illustrate the challenges in understanding SARS-CoV-2 transmission and in identifying infected individuals, tracing their contacts, and implementing preparedness plans. One of the absolute requirements, to clarify these questions and overcome these obstacles, is ensuring the prompt and large-scale testing of symptomatic individuals and of their asymptomatic contacts. This, together with the social distancing measures, are currently our only available assets in facing a pandemic that, even though it was preceded by multiple warnings in recent years, is unlike any other infectious disease that we experienced in modern history.

Specific therapies in pregnant women are discussedThe health crisis caused by the novel SARS-cov-2 (2019-nCoV) related pandemic requires urgent and necessary therapeutic response. Pregnant women are just as exposed as the general population and should not be excluded, because of their status, from discussions on effective and well tolerated candidate treatments. While in countries that have opted for national containment, daily non-emergency medical and surgical activities are suspended, obstetric services continue to operate relentlessly and are experiencing a surge in so-called ”at-risk” pregnancies. Some countries have now recommended routine screening of all pregnant women 1 but the low availability and performance of the current tests limits their use. Management of an infected pregnant women is essentially conditioned by maternal symptomatology. Women with little or no symptoms do not require routine treatment or in-patient care and simply need to be monitored for up to 15 days for evidence of respiratory deterioration. In the absence of validated specific treatment, the primary approach to therapy is mainly symptomatic and delivery is considered in the event of critical respiratory distress in order to maximize oxygenation and lung capacity2–4 . However, it has been reported that women with respiratory signs may be given antiviral treatment to improve their clinical condition 2,4To date, there is no proven effective strategy, although many teams are working tirelessly to identify an effective treatment. Four molecules are leading in this race:1) Remdesivir is a novel nucleotide analogue prodrug which incorporates into nascent viral RNA chains and results in pre-mature termination. Its effectiveness has been already demonstrated against others coronaviruses such as SARS-Cov and MERS-Cov5, and it has proven to be highly effective on in vitro 2019-nCoV infection6. Compassionate use in human were also reported 7 and phase 3 studies are currently underway.2) (Hydroxy)chloroquine has been known for years because of its effectiveness in the treatment of inflammatory diseases and against malaria. Recent studies have shown antiviral effects of chloroquine and in vitro studies concluded that it was highly effective in the control of 2019-nCoV 6,8. Elevation of endosomal pH and interference with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2 conduct to block virus infection. (Hydroxy)chloroquine has been used in 2019-nCoV infected humans with highly controversial restuls9,10 and well-designed randomized studies should be available soon.3) Lopinavir, a viral protease inhibitor, with its pharmacological booster Ritonavir (LPV/R) are commonly used in HIV positive patients. It has already been used for SARS-Cov. Some countries such as China and India approved its use in symptomatic infected patients although a first randomized, controlled, open-label trial showed no benefit of LPV/R over standard care in patients with severe 2019-nCoV disease11.4) Ribavirin, is a guanosine analog that interferes with the replication of RNA and DNA viruses. It has been used for years in the treatment of chronic hepatitis C. Based on its direct anti‐viral activity against 2019‐nCoV in vitro and some evidence for its potential efficacity during the prior SARS-Cov and MERS-Cov outbreaks, it has been suggested as a potential candidate for the treatment of 2019-nCoV diease12. 2019-nCoV infected patients treated with Ribavirin have been reported by Chinese studies4,13but its exact benefit remains to be demonstrated in well designed randomized studies as well.To date, all four drugs are being independently tested in Phase 3 studies, mostly national, to investigate their efficacy and safety in the management of 2019-nCoV disease. Several European countries have also set up, as a result of joint efforts since mid-March, a randomized, multicentre, open-label trial to evaluate and compare the efficacy and toxicity of the first three treatments mentioned above.14With regard to the possibility of treating pregnant patients with these molecules, few data are available for Remdesivir. Only one study reports its use in six pregnant women in a randomized trial during Ebola epidemics. The authors reported no adverse effect15.Many more pharmacological studies on maternal-fetal tolerance of Hydroxy(chloroquine), Lopinavir and Ribavirin are available. The historical use of (hydroxy)chloroquine in antimalarial treatment, but also in connective tissue diseases, has resulted in a well-documented safety and tolerance profile in pregnant women16. Animal studies, undertaken during the Zika virus epidemic, have also suggested that chloroquine may also reduce the risk of viral transplacental transmission to the fetus17. The optimal dosage to be used in pregnant women will have to be specified, but it appears that there is no pharmacokinetic difference between chloroquine and its major metabolite between pregnant and non-pregnant women18. With respect to the use of protease inhibitors during pregnancy, such as Lopinavir, some teams have reported an increased risk of preterm delivery. However, a specific analysis of more than 4,000 pregnant women found a similar incidence and rate of adverse pregnancy outcomes than in controls at all three trimesters of pregnancy, including preterm birth, low birth weight and birth defects19. Significant teratogenic effects have been demonstrated in all animal species exposed to Ribavirin, it is therefore currently contraindicated in pregnant women and in their male sexual partners, although the ribavirin pregnancy registry did not bring evidence of teratogenicity in humans20.The use of antiviral therapy in infected pregnant patients should follow the same indication as in the general population, but some obstetric specificities should be emphasized.1) The main goal should be to slow down and at best stop the clinical progression of the disease, i.e to remain asymptomatic and to avoid progression to acute respiratory distress syndrome in symptomatic cases. In the latter, the obstetrician is often called on to perform an emergency delivery and thus to induce extreme prematurity. Expert consensus provided obstetric guidance, but the management of cases at between 25 and 32 weeks’ remains challenging in the absence of effective antiviral treatment1.2) The second objective would be to rapidly decrease viral load and duration of contagiousness in infected pregnant women. The majority of them are doing well, but the infection can disrupt their obstetrical calendar. Some procedures need to be performed at a specific age, such as first trimester serum markers, ultrasound examinations, chorionic villi sampling (CVS). The same applies to access to termination of pregnancy. All such procedures may indeed be delayed, either to limit contagion, to limit the burden on the health care team (due to reinforced barrier measures…) or in the particular case of CVS/amniocentesis, to limit the theoretical risk of fetal transmission.3) Finally, the third advantage could be to introduce preventive treatment in case of maternal contact with an infected person, similar to what is done for seasonal influenza and oseltamivir21.The use of immunotherapy such as Tocilizumab, plasma of recovered coronavirus patient, Interferons, were not discussed here as they are currently understudy only for critically ill COVID-19 patients. No place for these treatments in a patient who is still pregnant should be considered for the time being, since if the pregnant woman presents a very severe form, the birth will be considered as a priority.The results of the Phase 3 therapeutic studies should be available soon. However, it is unfortunate that infected pregnant women are not included in any appropriate research protocols. Consequently, in this period of pandemic, mutual exchanges of experience between all countries’ maternity hospitals must be carried out in order to ensure the best possible management of infected pregnant women.

Objectives: To investigate the mental status of pregnant women and to describe their obstetrical choices during the outbreak of COVID-19. Design: A cross-sectional study. Setting: Wuhan and Chongqing, two different epidemic areas. Population: A total of 1947 valid questionnaires were received. Methods: We collected information on demographic, pregnancy, and epidemic, along with their attitudes towards the epidemic, anxiety status and obstetrical choices. We described and compared the city-based distribution of all above factors, aiming to explain how anxiety and obstetrical choices existed and differed. Main Outcome Measures: To explore why differences existed, we estimated the impact of the epidemic on women’s anxiety by multivariable analysis. Results: Distribution differences could be seen between cities in employment status, household income, gestational age, fetal number, and exposure history. Women’s attitudes towards COVID-19 in Wuhan were more extreme than that in Chongqing. The anxiety rate was more than double in Wuhan (24.47%) compared to that in Chongqing (10.44%). Generally speaking, obstetrical choices were similar among the 1947 participants, but more obvious in Wuhan. Conclusions: Our study found that the outbreak aggravated prenatal anxiety, and the influence factors could be targets of mental care. Synchronously, vital obstetrical choices changed, followed by pertinent professional advice to prevent irreversible adverse pregnancy outcomes. Online platforms may play crucial roles to address patients’ needs in future PHEs. Funding: National Natural Science Foundation of China (No. 81771614 and No. 81771613), and the National Key Research and Development Program of China (No. 2016YFC1000407). Keywords: COVID-19; Pregnancy; Prenatal Anxiety; Obstetrical Choices.

Dear Editor,Thank you for the opportunity to respond to Dr Sahu’s letter1. We would like to thank Dr Sahu and his team for their valuable points and ourselves recognise and acknowledge the gaps in our early commentary2 which reflected on the early practice at our hospital, with an aim to help fellow obstetricians with the management of COVID-19 at the start of the outbreak. Since then, more literature has been published providing us with greater knowledge regarding this new infection. Guidance from the Royal College of Obstetricians and Gynaecologists (RCOG)3 and International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG)4 amongst others help us streamline management of COVID-19 in pregnant patients.Both guidelines concur that radiographic investigations should be performed in pregnant patients – protecting the fetus by using a radiation shield over the gravid uterus. Chest CT has high sensitivity up to 97% for diagnosis of COVID-19 and may be considered as primary tool for COVID-19 detection.Both guidelines recommend the use of antenatal corticosteroids (ANC) for the usual indications but cautions use in critically ill women with COVID-19 infection as it may worsen their clinical condition. Importantly, urgent deliveries should not be delayed for the administration of ANC.Li et al5 compared clinical characteristics, maternal and neonatal outcomes of pregnant women with and without COVID-19. They found that COVID-19 infection generally causes mild respiratory symptoms in pregnant women, with no deaths or severe respiratory complications requiring critical care. They observed a higher rate of preterm deliveries in confirmed cases (33.3%) compared to control groups (¬5%). This study included two patients who had vaginal deliveries prior to COVID-19 diagnosis. Their newborns did not show any respiratory symptoms.New reports of SARS-COV-2 IgM in infants6 at birth suggest possibility of vertical transmission although COVID-19 infection in newborns is more commonly likely due to neonatal transmission.During breastfeeding, the main risk for infants lies in their close contact with mothers and transmission of infective respiratory droplets. Infected mothers wishing to breastfeed should do so with precautions such as wearing surgical masks, practising good hand hygiene and thorough cleaning of equipment after use. While the decision for separation of mother and baby has serious consequences on bonding and mental health, we continue to advise separation of baby from mothers infected with COVID-19 due to risk of neonatal transmission.Current data suggests that the adverse effects of COVID-19 in pregnancy are less severe than those of SARS-CoV and MERS-CoV. All presently reported patients were diagnosed in the third trimester and the potential effects of COVID-19 infections in the first and second trimesters remain to be investigated.As Dr Sahu mentioned, comparative studies are scarce. Establishment of international registries will improve our understanding of COVID-19 in pregnancy. Meanwhile, we shall continue to support one another and work together in the fight against this pandemic.We would like to thank the all departments from the Division of Obstetrics and Gynaecology, Infectious Diseases Department and all staff in KK Womens’ and Children’s Hospital for leading the COVID-19 fight locally.Monica Shi Qi Chua1, Jill Cheng Sim Lee2, Suzanna Sulaiman1, Hak Koon Tan31Department of Obstetrics and Gynaecology,2Department of Urogynaecology,3Division of Obstetrics and GynaecologyKK Women’s and Children’s Hospital, Singapore

Background: The corona virus disease 2019 (COVID-19) outbreak originating in Wuhan, Hubei province, China, coincided with chunyun, the period of mass migration for the annual Spring Festival. To contain its spread, China adopted unprecedented nationwide interventions on January 23 2020. These policies included large-scale quarantine, strict controls on travel and extensive monitoring of suspected cases. However, it is unknown whether these policies have had an impact on the epidemic. We sought to show how these control measures impacted the containment of the epidemic. Methods: Web of Science database was searched on February 26, 2020 for Corona virus (COVID-19) publications published between 1997 to 2020. It was performed on the same day in order to avoid the possible bias came from update on the database because the metrics are changing over time. All publication types were considered; however publications as errata were excluded. Analysis parameters include year of publication, publication type, patterns of international collaboration, research institutions, journals, impact factor, h-index, language, and times cited. Results: A total of 12612Corona virus (COVID-19) research publications were published across the world. The Corona virus (COVID-19) associated publications were originated from 25 countries/territories, indicating the international spread of Corona virus (COVID-19) research. The USA was the largest contributor, with 4524 articles published over 32 years, followed by Peoples R China(2667 articles). The total number of citations for these publications has already achieved 8,015, with an average of 9.01 citations per each publication. The h-index for Corona virus (COVID-19) -associated publications was 48. The USA also have the highest h-index (32), followed by KSA (26) and UK (22). Netherland produced the greatest proportion of publications with international research collaboration (72.7 %) followed by the UK (71 %) and Germany (69.1 %) out of the total number of publications for each country.

COVID-19 pandemic disease spread by SARS-COV-2 single-strand structure RNA virus belongs to the 7th generation of the coronavirus family. Following an unusual replication mechanism, its extreme ease of transmissibility has put many counties under lockdown. With a cure for the infection uncertain in the near future, the pressure currently lies in the current healthcare infrastructure, policies, government activities, and behaviour of the people to contain the virus. This research seeks to understand the spreading patterns of the COVID-19 virus through exponential growth modelling and identifies countries that have showed an initial sign of containment until 26th March 2020. Post identification of countries that have shown an initial sign of containment, predictive supervised machine learning models were built with infrastructure, environment, policies, and infection related independent variables. For the purpose, COVID-19 infection data across 42 countries were used. Logistic regression results shows a positive significant relationship of healthcare infrastructure and lockdown policies on the sign of early containment in countries. Machine learning models based on logistic regression, decision tree, random forest, and support vector machines were developed and are seen to have accuracies between 76.2% to 92.9% to predict early sign of infection containment. Other policies and activities taken by countries to contain the infection are also discussed.